CN115969824A - 紫草萘醌衍生物及其与抗生素联用在制备治疗细菌感染疾病药物中的用途 - Google Patents
紫草萘醌衍生物及其与抗生素联用在制备治疗细菌感染疾病药物中的用途 Download PDFInfo
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- CN115969824A CN115969824A CN202310193297.7A CN202310193297A CN115969824A CN 115969824 A CN115969824 A CN 115969824A CN 202310193297 A CN202310193297 A CN 202310193297A CN 115969824 A CN115969824 A CN 115969824A
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- lithospermum
- bacteria
- acetylshikonin
- naphthoquinone derivative
- derivative
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Abstract
本发明公开了紫草萘醌衍生物及其与抗生素联用在制备治疗细菌感染疾病药物中的用途。在体内外对革兰氏阳性菌有很好的抗菌效果，并且可以恢复多粘菌素或美罗培南耐药菌的敏感性，是实现抗生素替代和解决细菌耐药性问题的策略之一。
Description
技术领域
本发明涉及紫草萘醌衍生物制药新用途，特别涉及紫草萘醌衍生物及其与抗生素联用在制备治疗细菌感染疾病药物中的用途。
背景技术
近年来，随着抗菌药的广泛应用，耐药性问题日渐凸显，多药耐药细菌的快速出现及迅速传播，使得全球公共卫生系统面临重大威胁。更严重的是，由于新型抗菌药的研发耗时长、花费高、投资回报率低等原因，新型抗生素的开发管道自二十世纪90年代末以来一直处于枯竭状态，新型抗菌药的研发速度已远远落后于耐药性的发展速度，使得人类进入后抗生素时代。基于“one health”的理念，全球推行了一系列“减抗限抗”的行动计划。在此耐药性发展迅速，新型抗生素研发不足的“后抗生素时代”及“减抗限抗”背景下，迫切需要新型的抗菌策略去应对日益严重的抗生素危机。
植物占据地球上最大的生物量，进化出了很多类似药物功能的次级代谢物以应对感染。据报道，从1981年到2010年，大约65％的批准药物要么属于天然化合物，要么属于它们的半合成衍生物。截止到2018年，FDA共收到800余份植物药物的研究申请或会前申请，并批准了两项植物新药申请(茶多酚和Fulyzaq)。表明植物源小分子是一种很有前途的抗菌先导化合物来源。且天然化合物确实的作用效果、结构的多样性，来源的丰富性、作用的安全性提示我们，从植物中寻找具有“抗菌”或“协同增效”活性的小分子天然化合物，通过与现有重要抗菌药配伍使用从而提高其抗菌效果，使其恢复对多重耐药病原菌的敏感性，是目前解决细菌耐药性问题的重要策略之一。
紫草的主要成分可分为两类，一类是脂肪酸，另一类则是萘醌及其衍生物如紫草素、乙酰紫草素(ASK)、去氧紫草素、异丁酰紫草素等。紫草萘醌衍生物的抗菌活性还未知。而有关于紫草萘醌衍生物与其他抗生素是否具有协同增效作用也有待进一步阐明。
发明内容
发明目的：本发明目的是提供紫草萘醌衍生物在制备治疗细菌感染疾病药物中的用途。
本发明目的是提供紫草萘醌衍生物及其与抗生素联用在制备治疗细菌感染疾病药物中的用途。
技术方案：本发明提供紫草萘醌衍生物在制备治疗细菌感染疾病药物中的用途。
进一步地，紫草萘醌衍生物包括去氧紫草素、紫草素、乙酰紫草素、β，β-二甲基丙烯酰紫草素、β-羟基异戊酰紫草素，结构如下：
进一步地，所述细菌为革兰氏阳性菌，所述革兰氏阳性菌包括金黄色葡萄球菌、粪肠球菌、屎肠球菌、表皮葡萄球菌等。
紫草萘醌衍生物与抗生素联用在制备治疗多药耐药革兰氏阴性菌感染引起的疾病药物中的用途。
进一步地，紫草萘醌衍生物包括去氧紫草素、紫草素、乙酰紫草素、β，β-二甲基丙烯酰紫草素、β-羟基异戊酰紫草素。
进一步地，所述多药耐药革兰氏阴性菌对多粘菌素(COL)或美罗培南(MER)耐药。
有益效果：本发明与现有技术相比，具有如下优势：本发明提供了紫草萘醌衍生物作为抗菌药物的用途，在体内外对革兰氏阳性菌有很好的抗菌效果，并且可以恢复多粘菌素或美罗培南耐药菌的敏感性，是实现抗生素替代和解决细菌耐药性问题的策略之一。
附图说明
图1乙酰紫草素快速杀灭金黄色葡萄菌结果图；
图2乙酰紫草素可以增强多粘菌素及美罗培南对耐药大肠杆菌的杀灭活性结果图；
图3乙酰紫草素对红细胞没有或具有微弱的溶血活性结果图；
图4乙酰紫草素显著提高了大蜡螟幼虫的存活率结果图；
图5乙酰紫草加速了伤口感染模型的愈合并显著减少了载菌量结果图；
图6乙酰紫草破坏金黄色葡萄球菌的形态结果图；
图7乙酰紫草破坏金黄色葡萄球菌的细胞膜消散膜电势降低胞内ATP水平结果图。
具体实施方式
1、紫草萘醌衍生物的抗菌谱及最小抑菌浓度测定
采用微量肉汤稀释法测定紫草萘醌衍生物的抗菌活性，紫草萘醌衍生物购买自成都普瑞法科技开发有限公司，包括：紫草素(货号：517-89-5)、去氧紫草素(货号：43043-74-9)、乙酰紫草素(货号：43043-74-9)、β-羟基异戊酰紫草素(货号：7415-78-3)、β，β-二甲基丙烯酰紫草素(货号：24502-79-2)。测试菌株见表1，包括敏感菌以及携带不同耐药基因的多重耐药菌，尤其是目前临床最为严重的耐甲氧西林金黄色葡萄球菌(MRSA)、万古霉素耐药肠球菌(VRE)、携带optrA或poxtA的利奈唑胺耐药肠球菌等都有较好的抗菌活性。
表1菌株信息
注：文献1为Liu Y，Ding S，Dietrich R，
E，Zhu K.A biosurfactantinspired heptapeptide with improved specificity to kill MRSA[J].AngewandteChemie International Edition，2017，56(6)，1486-1490.
文献2为Meirong Song，Yuan Liu，Xiaoyong Huang，Shuangyang Ding，YangWang，Jianzhong Shen and Kui Zhu.A broad-spectrum antibiotic adjuvant reversesmultidrug-resistant Gram-negative pathogens.Nat.Microbiol.，2020，5(8)：1040-1050.
文献3为Fioriti S，Morroni G，Coccitto SN，Brenciani A，Antonelli A，DiPilato V，Baccani I，Pollini S，Cucco L，Morelli A，Paniccià M，Magistrali C F，Rossolini GM，Giovanetti E.Detection of Oxazolidinone Resistance Genes andCharacterization of Genetic Environments in Enterococci of Swine Origin，Italy.Microorganisms.2020 Dec 17；8(12)：2021.
文献4为Dejoies L，Sassi M，Schutz S，Moreaux J，Zouari A，Potrel S，ColletA，Lecourt M，Auger G，Cattoir V.Genetic features of the poxtA linezolidresistance gene in human enterococci from France.J Antimicrob Chemother.2021Jul 15；76(8)：1978-1985.
文献5为YIN Y，QIU L，WANG G，et al.Emergence and Transmission ofPlasmid-Mediated Mobile Colistin Resistance Gene mcr-10 in Humans andCompanion Animals[J].Microbiol Spectr，2022，10(5)：e0209722.
微量肉汤稀释法具体步骤如下：
(1)用CAMHB肉汤培养基(海博生物技术有限公司，HB6231-1)稀释待测菌株的菌液，使细菌悬液浓度为1×106CFU/mL。
(2)取紫草萘醌衍生物，分别用二甲亚砜(DMSO)溶解并用CAMHB肉汤培养基稀释，分别得到浓度为512μg/mL的紫草素、去氧紫草素、乙酰紫草素、β-羟基异戊酰紫草素、β，β-二甲基丙烯酰紫草素抗菌药物溶液。利奈唑胺和万古霉素溶解在超纯水中，制备得到浓度为2560μg/mL的储备液，使用时用CAMHB稀释至试验需要的浓度。
(3)取96孔板，每孔加入100μL CAMHB肉汤培养基，第一列每孔加入100μL步骤(2)制备的抗菌药物溶液，自第一列倍比稀释至第十列；之后每孔加入100μL步骤(1)制备的菌悬液，37℃静置培养18h。设置阳性对照和阴性对照孔，每个阳性对照孔加入100μL步骤(1)制备的菌悬液，阴性对照只含CAMHB肉汤培养基。
试验结果见表2，五种紫草萘醌衍生物对革兰氏阳性敏感菌和耐药菌均表现出一定的抗菌活性，最小抑菌浓度介于0.5～64μg/mL。以乙酰紫草素的抗菌活性最强，最小抑菌浓度介于0.5-8μg/mL。比较几种化合物的结构发现，11位碳上的羟基乙酰化对于提
高紫草素的抗菌活性具有重要的意义。
表2五种紫草源萘醌类化合物对G+的抗菌作用
实施例2、紫草萘醌衍生物与抗生素的协同抗菌活性
采用棋盘稀释法测定紫草萘醌衍生物和抗生素联合使用对多重耐药大肠杆菌(Escherichia coli)B2(blaNDM-5+mcr-1)、沙门菌(Salmonella)15E343(mcr-3)、肺炎克雷伯菌(K.Pneumoniae)19-2-1(mcr-8)、大肠杆菌(Escherichia coli)ATCC 25922的协同抗菌活性。
棋盘稀释法具体步骤如下：
(1)用CAMHB肉汤培养基稀释待测菌株的菌液，使细菌悬液浓度为1×106CFU/mL。
(2)抗生素以CLSI准则推荐的溶剂溶解并用CAMHB肉汤培养基稀释，得到浓度为256μg/mL的抗生素溶液。具体来说，粘菌素、美罗培南、四环素、替加环素、卡那霉素和环丙沙星分别溶解在超纯水中，分别制备得到浓度为2560μg/mL的储备液，氨苄西林溶解在0.1M的PBS(pH＝8)中，用超纯水稀释得到浓度为2560μg/mL的储备液，利福平用甲醇溶解后在超纯水中稀释至2560μg/mL，使用时用CAMHB稀释储备液至试验需要的浓度。
(3)紫草萘醌衍生物溶液的配制：分别用二甲亚砜(DMSO)溶解并用CAMHB肉汤培养基稀释，分别得到浓度为256μg/mL的紫草素、去氧紫草素、乙酰紫草素、β-羟基异戊酰紫草素、β，β-二甲基丙烯酰紫草素抗菌药物溶液。
(4)取96孔平底板，每孔加入100μL CAMHB肉汤培养基，最后一行每孔加入100μL步骤(2)中制备的抗生素溶液，自第八行倍比稀释至第二行；第一列每孔加入步骤(3)制备的紫草萘醌衍生物溶液(每孔100μL)，倍比稀释至第七列，之后每孔加入100μL步骤(1)制备的细菌悬液，37℃静置培养18h，观察紫草萘醌衍生物和多粘菌素联合使用抑制细菌生长的最低浓度组合。
分级抑菌浓度(FICI)计算方法如下：
FIC＝MIC(A药联合)/MIC(A药单用)+MIC(B药联合)/MIC(B药单用)
实验结果如表3所示，乙酰紫草素对氨苄西林、四环素、替加环素、利福平、环丙沙星及卡那霉素无协同作用，其分级抑菌浓度指数(FICI)均为2。而与多粘菌素、美罗培南的FICI分别为0.04、0.09，可以使多粘菌素、美罗培南的MIC降低32倍，乙酰紫草素与多粘菌素及美罗培南的协同作用明显。
表3乙酰紫草素与不同类型抗生素对大肠杆菌B2的协同抗菌作用
a抗生素单独使用时对耐药菌的最小抑菌浓度；b加入乙酰紫草素后不同种类抗生素对耐药菌的最小抑菌浓度；c抗生素的抗菌活性提高倍数。
实施例3、乙酰紫草素时间杀菌曲线
金黄色葡萄球菌ATCC 29213在CAMHB肉汤培养基中37℃培养至指数期，用CAMHB肉汤稀释菌液至106CFU/mL的理想浓度。加入4μg/mL(4×MIC)的乙酰紫草素，于37℃培养，分别在0、2、5、10、15min后取50μL菌液，按10倍顺序稀释，滴在LB琼脂(海博生物技术有限公司，HB0129)平板上，在37℃培养24h后计算菌落形成单位(CFU/mL)。
大肠杆菌B2在CAMHB肉汤培养基中37℃培养至指数期，用CAMHB肉汤稀释菌液至106CFU/mL的理想浓度。然后分别用乙酰紫草素(32μg/mL)和多粘菌素(2μg/mL)或美罗培南(8μg/mL)单独或联合处理细菌，分别在0、4、8、12、24h取50μL菌液，10倍顺序稀释后滴在LB琼脂平板上，在37℃培养24h后计算菌落形成单位(CFU/mL)。所有实验都至少进行了3次生物重复。
结果表明，乙酰紫草素对金黄色葡萄球菌具有快速的杀菌作用，在15分钟时即可杀灭99％的细菌(图1)。并且乙酰紫草素(ASK)可增强多粘菌素(COL)以及美罗培南(MER)对耐药菌的杀菌效果，联合作用下在4h内即可杀灭所有细菌(图2)。
实施例4、乙酰紫草素的溶血性分析
为评价乙酰紫草素的安全性，评估了乙酰紫草素的溶血活性。在96孔平板中从1孔至10孔将乙酰紫草素用磷酸盐缓冲液(PBS)(10mM，pH＝7.4)倍比稀释，11孔以灭菌的PBS为阴性对照，12孔以双蒸水(ddH2O)为阳性对照。新鲜绵羊红细胞(RBC)(北京索莱宝科技有限公司，TX0030)用PBS(10mM，pH＝7.4)洗涤两次后用PBS(10mM，pH＝7.4)重悬，制得8％红细胞悬浮液，将红细胞悬浮液与浓度为0.5、1、2、4、8、16、32、64、128μg/mL的乙酰紫草素混合，在37℃下孵育1h。之后，吸取120μL上清液3000rmp/min离心10min，吸取100μL测量释放的血红蛋白在576nm(OD576)处的吸光值，计算相应的溶血率。溶血率的计算如下所示：溶血率(％)＝[(OD576样品-OD576阴性对照)/(OD576阳性对照-OD576阴性对照)]×100％。实验结果如图3所示，即使在128μg/mL的高浓度下，乙酰紫草素也表现出低的溶血率(5.5％)。
实施例5、乙酰紫草素治疗大蜡螟幼虫耐甲氧西林金黄色葡萄球菌感染
(1)乙酰紫草素用DMSO溶解配成2560μg/mL的储备液，用PBS(10mM，pH＝7.4)稀释成50、150μg/mL的工作液。
(2)金黄色葡萄球菌MRSAT144接种于LB肉汤培养基，置于37℃培养到对数生长期。用PBS(10mM，pH＝7.4)缓冲液重悬MRSAT144使菌液浓度均为105CFU/mL。
(3)取50只体重300mg左右的大蜡螟幼虫随机分成4组，分别在左下最后1个腹足注射10μL步骤(2)中的菌液，感染1h后分别在右下最后1个腹足注射浓度10μL50、150μg/mL的乙酰紫草素，对照组给予10μL的PBS(10mM，pH＝7.4)。
(4)在12、24、36、48h统计大蜡螟幼虫的存活率。
实验结果见图4。50μg/mL的乙酰紫草素治疗可以使MRSA感染的大蜡螟存活率提高至70％，150μg/mL的乙酰紫草素治疗后90％的大蜡螟存活。
实施例6、乙酰紫草素治疗大鼠皮肤创口感染
以金黄色葡萄球菌MRSA T144为模式菌构建大鼠皮肤创口感染模型，评价乙酰紫草素对革兰氏阳性菌感染的治疗效果。乙酰紫草素用DMSO溶解配成2560μg/mL的储备液，用PBS(10mM，pH＝7.4)稀释成10、20、50μg/mL的工作液。金黄色葡萄球菌MRSAT144接种于LB肉汤培养基(海博生物技术有限公司，HB6231-1)，置于37℃培养到对数生长期。用PBS(10mM，pH＝7.4)缓冲液重悬MRSA T144使菌液浓度均为108CFU/mL。将wistar大鼠(扬州大学比较医学中心)分为10、20、50μg/mL的乙酰紫草素处理组和对照组4个组。用灭菌的手术剪在大鼠背部剪开一个1cm2左右的创口。随后用100μL(108CFUs/mL)的MRSA T144细菌悬液造成创口感染，感染一小时后给予100μL不同浓度(浓度分别为10、20、50μg/ml)的乙酰紫草素治疗，对照组给予PBS(10mM，pH＝7.4)。连续12天观察大鼠背部创口愈合情况并测量创口尺寸变化，最后一天将大鼠安乐死，取大鼠右创口皮肤(1cm2)匀浆稀释后稀释滴板进行菌落计数。实验结果见图5。乙酰紫草素可以显著促进伤口的愈合，并且使皮肤创口的载菌量降低约100倍(107CFUs/mL降至105CFUs/mL)。
实施例7、金黄色葡萄球菌形态观察
金黄色葡萄球菌MRSA T144在25mL MHB培养基(海博生物技术有限公司，HB6231-1)中37℃培养过夜，然后以5000rpm和4℃离心5min，用PBS(10mM，pH＝7.4)洗涤。然后与5(10*MIC)或10μg/ml(20*MIC)的乙酰紫草素(ASK)共孵育。随后，用PBS(10mM，pH＝7.4)洗涤3次，用2.5％戊二醛固定，4℃过夜。次日，用不同浓度的乙醇(30％、50％、70％、90％、100％)脱水细菌。最后，将细菌干燥、电镀、黏附后，用GeminiSEM 300电子显微镜对样品进行观察。实验结果见图6。乙酰紫草素处理后金黄色葡萄球菌MRSA T144的形态结构被破坏。
实施例8、乙酰紫草素杀菌机制研究
金黄色葡萄球菌MRSA T144在LB培养基中37℃过夜培养，在25ml LB培养基中1∶100稀释并扩培到对数生长期。用PBS(10mM，pH＝7.4)洗涤3次，将细菌悬液OD600值调整为0.5左右。用荧光探针在37℃避光孵育30分钟得到探针标记的细菌。将190μL探针标记的细菌加入96孔板中，与10μL不同浓度的ASK(浓度分别为0.5、1、2、4μg/ml)孵育1h。使用Infinite M200酶标仪(Tecan)测量荧光值。碘化丙啶(PI)(上海碧云天生物技术有限公司，ST512)用于测量细菌细胞膜通透性。激发波长为535nm，发射波长为615nm。3,3-二丙基硫氰基碘化钠(disc3(5))(上海阿拉丁生化科技股份有限公司，53213-94-8)用于测量细菌的膜电势。激发波长为622nm，发射波长为670nm。对照为PBS。用PH敏感荧光探针BCECF-AM(上海碧云天生物技术有限公司，S1006)评价细菌的ΔpH。激发波长在488nm和发射波长为535nm。
细菌胞内ATP测定：使用增强ATP检测试剂盒(上海碧云天生物技术有限公司，S0027)测定ASK作用后金黄色葡萄球菌MRSAT144的胞内ATP水平。金黄色葡萄球菌MRSAT144在37℃振荡培养过夜，随后用PBS(10mM，pH＝7.4)清洗并重悬使OD600nm在0.5左右。然后用不同浓度的ASK(浓度分别为0.5、1、2、4μg/ml)处理菌悬液10min，然后4℃10 000rpm离心5min，溶菌酶裂解离心的细菌沉淀物用于测定细胞内ATP水平。将检测溶液加入96孔板中，室温孵育5min。加入上清液并快速混合，使用Infinite M200酶标仪(Tecan)测定luminescence。
结果如图7所示。乙酰紫草素增大细菌细胞膜通透性，消散质子驱动力，降低胞内ATP水平。提示乙酰紫草素通过膜破坏介导对细菌的杀灭。
Claims (7)
1.紫草萘醌衍生物在制备治疗细菌感染疾病药物中的用途。
2.根据权利要求1所述的用途，其特征在于，紫草萘醌衍生物包括去氧紫草素、紫草素、乙酰紫草素、β，β-二甲基丙烯酰紫草素或β-羟基异戊酰紫草素中的一种或几种。
3.根据权利要求1所述的用途，其特征在于，所述细菌为革兰氏阳性菌。
4.紫草萘醌衍生物与抗生素联用在制备治疗多药耐药革兰氏阴性菌感染引起的疾病药物中的用途。
5.根据权利要求4所述的用途，其特征在于，紫草萘醌衍生物包括去氧紫草素、紫草素、乙酰紫草素、β，β-二甲基丙烯酰紫草素、β-羟基异戊酰紫草素中的一种或几种。
6.根据权利要求4所述的用途，其特征在于，所述多药耐药革兰氏阴性菌包括对多粘菌素或美罗培南耐药的细菌。
7.根据权利要求6所述的用途，其特征在于，所述多药耐药革兰氏阴性菌包括金黄色葡萄球菌。
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